Inflammatory bowel disease (IBD) is etiologically classified into either the specific diseases or nonspecific diseases. Examples of the specific diseases include ischemic colitis and the inflammatory bowel syndrome caused by infection, drugs, chemicals or radiation. In contrast, the nonspecific diseases are also called as idiopathic inflammatory bowel syndrome and broadly classified into colitis (especially, ulcerative colitis (UC)) and Crohn's disease (CD)).
Ulcerative colitis mainly develops in adults aged 30 or under, but it sometimes develops in children or adults aged 50 or older. It forms erosions and ulcers in a mucosal layer or submucosal layer of the large intestinal mucosa, and the clinical symptoms thereof include distinguishing findings such as diarrhea, blood feces, stomachache and weight loss. Though ulcerative colitis was a traditionally relatively rare disease in our country, the number of the patients is increasing rapidly year by year in accordance with recent westernized diet. As the trigger thereof, various causes are thinkable such as enteric bacterial infection theory, dietary allergy theory, vascular disorder theory, autonomic disorder theory and immune abnormality theory, but the details are still unspecified and the fundamental method of the treatment has not yet been established at present.
Crohn's disease mainly develops in young adults, and it is composed of granulomatous inflammatory lesions accompanying fibrillation and ulcers. It is a chronic inflammatory disease which can develop in any area of digestive tubes. Crohn's disease is classified by its lesion area into gastroduodenal type, small bowel type, small and large bowel type, large bowel type, rectum type or subtype. Further, the disease is also classified by its activity determined from CDAI (crohn's disease activity index) classification (by National Cooperative Crohn's Disease Study Group) into the inactive stage, active stage, or extremely seriously ill. The clinical symptoms thereof include the symptoms such as stomachache, diarrhea, fever, anus abnormality like hemorrhoid, and weight loss. Histologically, the strong infiltration of lymphocytes and noncaseating epithelioid granuloma are observed. The detailed causes of Crohn's disease as well as those of ulcerative colitis have not been specified yet.
As for the drug therapy of inflammatory bowel syndrome, for example, steroid hormone, budesonide that is a synthetic steroid and the like are administered to patients with Crohn's disease in the hope of the effect of remission induction. However, there was a problem that side effects occur, such as bone loss, impaired glucose tolerance, hypertension, infections, glaucoma, cataract and gastric ulcer, due to the administration of steroids. In addition to it, salazosulfapyridine (SALAZOPYRINE; 6-oxo-3-((4-(pyridin-2-ylsulfamoyl)phenyl)hydrazinylidene]cyclohexa-1,4-diene-1-carboxylic acid) is administered in the hope of the effect against lesions of the large bowel, but it is reported that there are side effects such as nausea, headache, fever, eruption, hemolytic anemia, epidermal peeling, granulocytopenia, fibrous alveolitis, pancreatitis and male sterility.
In recent years, it has been clarified that inflammation occurs from the interaction between various substances and cells in vivo. It is thought that monocytes and lymphocytes aggregating to an inflammatory site relate to mucosal damages, and inflammatory mediators produced from these cells, especially cytokines are drawn attention to. Among them, TNF-α (Tumor Necrosis Factor-α) is one of the cytokines released from leucocytes and the substance that plays an important role on the defensive function in vivo, but it is also known as the substance that induces and exacerbates the inflammation when released excessively. Since the production of TNF-α increases in the patients with inflammatory bowel syndrome, drugs for inhibiting or neutralizing the production thereof, especially (genetically-modified) Infliximab (Patent Literature 1) of antihuman TNF-α antibody is used to the patients with Crohn's disease in the active stage and with the fistulae (external fistulae) as the drug having the effects such as the improvement of Crohn's disease symptoms and closure of the external fistula (trade name: REMICADE® (trademark) for intravenous drip infusion 100, Tanabe Seiyaku Co., Ltd.; a chimeric mouse/human monoclonal antibody, general name: Infliximab) (Non-patent Literature 2).
Meanwhile, as the antihuman TNF-α antibody decreases immune activity, the careful administration thereof is needed, keeping in mind of infections such as tuberculosis, sepsis, pneumonia and opportunistic infection; or allergic reactions and delayed hypersensitivity. Though the effect of decreasing Crohn's disease activity index (CDAI) is seen in the initial administration, since Crohn's disease requires the long-term continuing treatment and the repeated administration of anti-TNF-α antibody is needed in many cases, such effect is gradually lost, and it causes the problems such as increase in dosage and necessity to switch to the other drug therapies. Further, it has also been reported that the effect of Infliximab is not improved even if the administered dosage thereof is changed to 5, 10, 20 mg per 1 kg of body weight, for example. Therefore, it is necessary to examine the method for having the prolonged effect by small administration dosage. It is also necessary to introduce regression to acute inflammatory diseases in a short period and prolong the effect with inhibiting the expression of the side effects for long periods.
As mentioned above, in the conventional drug therapies including said steroid hormone to the patients with inflammatory bowel syndrome, it has been necessary to administer the drug carefully about the administration time, dosage, period and the like, corresponding to the conditions of the expression of the side effects. Besides, it is difficult to inhibit the inflammation of inflammatory bowel syndrome for long periods without serious side effects, and there were many clinical cases that the inflammation repeats or recurs.
[Patent Literature 1] WO92/16553
[Non-patent Literature 2] Present, D. H. et al., N Engl J Med., 340(18): 1398-1405, 1999